Prostate cancer is still one of the leading causes of death in men of developed countries including the U. S., despite of the recent progress in its diagnosis and treatment. Although the advanced tumors initially respond to therapies such as androgen ablation, anti-androgen or the taxane-based chemotherapy, most of them develop resistance and the disease relapses. Therefore, there is an urgent need for better understanding of the resistance mechanisms and to identify markers and therapeutic targets for personalized treatment and improving survival. Current evidence supports the notion that multiple diverse pathways and mechanisms drive tumor resistance to different therapies including chemoresistance. Therefore, it will be highly significant if key resistance driving factors that interface the seemingly complex arrays of pathways can be identified. This proposal is based on our recent identification of an epigenetic regulator/histone methylase protein as a key factor of prostate cancer cell survival, proliferation and tumor growth. It functions as a novel co-activator of AR and NF-kB for induction of cell survival, pro-inflammatory gene and kinase signaling programs. Interestingly, it is induced by chemotherapeutic drugs and is overexpressed in prostate cancer tumors with high Gleason scores. Here, we wish to establish its function in driving chemoresistance and elucidate its functional mechanism as a key activator of multiple pathways involved in therapeutic resistance. We will also examine the epigenetic regulator for the potential value as a prognostic marker and a therapeutic target.